The formation of cataracts is an intractable eye condition where an opacification of the lens is caused and which results in a loss of visual acuity. Various studies on a causal factor and mechanism of cataracts, and a treatment method therefor have been made. But at present, there are very few medical substances which are effective for cataracts.
It is reported that an increase of peroxide in the lens is related to a cause of cataracts and a chemical substance having suppressive effect on lipid peroxide formation is effective on treatment of cataracts (Current Eye Res., 5, 37 (1986)). It is also reported that protein denaturation is observed in lenses of cataract patients (Ophthalmology, 19, 1283 (1977)).
From the reports, a chemical substance which has suppressive effect on lipid peroxide formation in combination with protein stabilizing effect can be presumed to be especially useful for treatment of cataracts. A compound having the above both effects, however, has not been studied and the development of such a compound has been desired.
As the result of our precise study to find a compound having a suppressive effect on lipid peroxide formation in combination with a protein stabilizing effect, the inventors found that 3-oxo-1,4-benzothiazine derivatives, in which the 2nd-position was substituted by a benzylidene group and the 4th-position was substituted by an acidic group, which is tetrazolyl, phosphonyl or sulfonyl, and the phenyl ring of the benzylidene group was further substituted by hydroxy and lower alkyl groups, exhibited both effects.
Some of 3-oxo-1,4-benzothiazine derivatives having a benzylidene substituent at the 2nd-position, where the chemical structure is common to the basic structure of the compounds of this invention, were reported to show activitity as a herbicide (U.S. Pat. No. 3923709), a tranquilizer (Japanese Patent Publication No. 10671/1974) or a synthetic intermediate of benzothiazepine derivatives (Japanese Unexamined Patent Publication No. 72875/1985). The description in the publications, however, is limited to benzothiazine derivatives wherein the 4-th position of the benzothiazine ring is substituted by aminoalkyl or carboxyalkyl. Benzothiazine derivatives having an acidic substituent, except carboxy group, have not been reported. Further the prior art discloses neither a protein stabilizing effect nor a suppressive effect on lipid peroxide formation.
Japanese Unexamined Patent Publication No. 287077/1989 discloses2-benzylidene-3-oxo-1,4-benzothiazine derivatives which have an active oxygen elimination effect or a suppressive effect on lipid peroxide formation. In this publication, however, the substituent at the 4th-position is limited to a lower alkyl group and a protein stabilizing effect is not disclosed at all.
In the meantime, recently the utility of aldose reductase inhibitors for treatment of cataract has attracted attention. The compound of this invention also has an aldose reductase inhibiting effect and is very useful for the treatment of cataracts.